1. Field
This invention pertains to drug delivery systems generally and is more particularly directed to transdermal drug delivery systems and methods.
2. State of the Art
Devices for transdermal or percutaneous drug delivery are known in the art. Such devices include "patches" such as the Nitro-Dur.RTM. nitroglycerin transdermal infusion system marketed by Key Pharmaceuticals of Kenilsworth, N.J. This system consists of a "patch" containing nitroglycerin in acrylicbased polymer adhesives with a resinous cross-linking agent to provide a continuous source of nitroglycerin to the patient. The patches are available in various dosage strengths for delivering various amounts of nitroglycerin to the patient over a twenty-four hour period. These patches vary in size from five to thirty square centimeters (cm.sup.2). The rated release of the drug is dependent upon the area of the patch with 0.5 milligram (mg) being released for every square centimeter of patch per 24 hours. The patch is applied to any convenient skin area, especially the arm or chest.
Another transdermal patch is marketed by Noven Pharmaceutical of Miami, Fla. The Noven patch has been used with nitroglycerin and estrogen. It consists of a nonocclusive backing layer, a drug reservoir for containing the drug, a microporous rate controlling membrane which contacts the skin of the patient, and an adhesive formulation for keeping the patch in contact with the skin. Drug passes from the reservoir through the membrane, through the patient's skin, and into the bloodstream.
Another transdermal patch, Transderm SCOP.RTM., is used by CIBA Consumer Pharmaceutical Co. of Summit, N.J. It is a film 0.2 mm thick and 2.5 cm.sup.2, with four layers. Proceeding from the visible surface towards the surface attached to the patient's skin (FIG. 12), these layers are: (a) a backing layer of tan-colored, aluminized, polyester film; (b) a drug reservoir of scopolamine, mineral oil, and polyisobutylene; (c) a microporous polypropylene membrane that controls the rate of delivery of scopolamine from the system to the skin surface; and (d) an adhesive formulation of mineral oil (12.4 mg), polyisobutylene (11.4 mg) and scopolamine (1.5 mg). A protective peel strip of siliconized polyester, which covers the adhesive layer, is removed before the system is used. The inactive components, mineral oil and polyisobutylene, are not released from the system. The system is "programmed" to deliver 0.5 mg of scopolamine at an approximately constant rate of the systemic circulation over the three-day lifetime of the system. An initial priming dose of scopolamine, released from the adhesive layer of the system is believed to saturate the skin binding sites for scopolamine and bring the plasma concentration of scopolamine to the required steady state level. A continuous controlled release of scopolamine, which flows from the drug reservoir through the rate-controlling membrane, maintains the plasma level constant.
A similar system is also used by CIBA Pharmaceutical Company in its Transderm-Nitro.RTM. nitroglycerin. In this system, the rate controlling membrane is an ethylene/vinyl acetate copolymer membrane that is permeable to nitroglycerin, and the adhesive used is a hypoallergenic silicone adhesive.
Another system to deliver drugs through the skin of a patient is disclosed in French patent 2,556,218. This patent discloses "sticks" for roll-on application of a desired drug. These sticks contain, as components, an enzymatic penetrating agent, the desired drug, and various excipients. The enzymatic penetrating agents disclosed include alpha-chymotrypsin and hyaluronidase. Drugs disclosed for use with these sticks include aspirin, lidocaine, lutadine, vitamin A, and tetracycline. Excipients disclosed include sodium glycerol stearate. The desired drug, enzymatic penetrating agent, and excipient can be mixed together to form a homogeneous mixture.
Alternatively, the various components of the stick can be separated from one another in a manner that brings one component (e.g., enzymatic penetrating agent) immediately after the other (e.g., drug) in contact with the local application zone of the patient's skin for treatment (e.g. a solid stick can make up two longitudinal or concentric parts of one stick). The enzymatic penetrating agents increase the penetration of the desired drug through the patient's skin or mucous membrane.
Another transdermal drug delivery system is disclosed in French Patent No. 2,448,903. This system consists of at least one antibiotic, an enzyme, an antiinflammatory agent, and/or a local anesthetic agent, and/or a heteratolytic agent, and/or a mucolytic agent, and/or an emulsifying agent. Enzymes disclosed include hyaluronidase, streptokinase, streptodonase, trypsin, chymotrypsin, .alpha.-chymotrypsin; .alpha.-amylase, bromelain, papain, desoxyribonuclease, collagenase, and sutilain. This system is used to provide localized antibiotic therapy.
None of these prior art systems have fully utilized proteolytic enzymes' ability to increase an animal's skin's permeability to permit the transdermal delivery of a drug.